A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

Abstract

During development of the CNS, neurons and glia are generated in a sequential manner. The mechanism underlying the later onset of gliogenesis is poorly understood, although the cytokineinduced Jak-STAT pathway has been postulated to regulate astrogliogenesis. Here, we report that the overall activity of Jak-STAT signaling is dynamically regulated in mouse cortical germinal zone during development. As such, activated STAT1/3 and STAT-mediated transcription are negligible at early, neurogenic stages, when neurogenic factors are highly expressed. At later, gliogenic periods, decreased expression of neurogenic factors causes robust elevation of STAT activity. Our data demonstrate a positive autoregulatory loop whereby STAT1/3 directly induces the expression of various components of the Jak-STAT pathway to strengthen STAT signaling and trigger astrogliogenesis. Forced activation of Jak-STAT signaling leads to precocious astrogliogenesis, and inhibition of this pathway blocks astrocyte differentiation. These observations suggest that autoregulation of the Jak-STAT pathway controls the onset of astrogliogenesis.During embryonic development, the generation of three major neural cell types (neurons, astrocytes, and oligodendrocytes) in the CNS occurs sequentially, whereby almost all neurons are generated before the appearance of glial cells 1,2 , with the exception of a few COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2014 November 06. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sites of postnatal and adult neurogenesis such as the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the forebrain 3 . This strategy of building the CNS through sequential production of neurons and glia has become more comprehensible, as recent findings have demonstrated that glial cells are important in critical neuronal maturation processes such as axonal path finding and synapse formation [4][5][6] . It is conceivable that delayed or precocious production of glial cells may lead to inappropriate wiring, disorganization, and eventually, dysfunction of the CNS.The 'neurons-first, glia-second' differentiation theme for neural progenitors can be recapitulated in culture. Cortical neural progenitor stem cells isolated from relatively early embryonic stages (for example, mouse embryonic day (E) 10-11) give rise to neurons, not glial cells, after short-term culturing (fewer than 4 d), whereas cortical progenitors isolated from perinatal stages tend to differentiate into astrocytes under the same culture conditions 7 .In addition, both E10-11 cortical progenitors and embryonic stem cell-derived neural stem or progenitor cells (NSCs or NPCs) switch from being neurogenic to gliogenic over time in vitro 8,9 , suggesting that the molecular switch for the transition from neurogenesis to gliogenesis may be internally programmed in neural progenitors.S...

Direct Evidence of Astrocytic Modulation in the Development of Rewarding Effects Induced by Drugs of Abuse

“…The Jak/STAT pathway modulates astrogliosis and/or astrogliogenesis (Bonni et al, 1997;Sriram et al, 2004;He et al, 2005). It should be mentioned that ACM, but not METH itself, induced the differentiation of NSCs into GFAP-positive astrocytes via the Jak/STAT pathway.…”

“…In addition, the Jak/STAT pathway has been postulated to regulate astrogliosis and astrogliogenesis (Bonni et al, 1997;Sriram et al, 2004;He et al, 2005). The place preference produced by MRP (3 mg/kg, s.c.), was significantly suppressed by intra-N.Acc.…”

Involvement of the Mouse Prp19 Gene in Neuronal/Astroglial Cell Fate Decisions

“…Furthermore, the forced expression of the EGF receptor in early progenitors induces precocious astrocyte differentiation in response to LIF by increasing STAT3 protein levels (68), showing that, during the neurogenic period, the Jak/STAT pathway is only weakly activated. Recently, He et al (41) reported a positive autoregulatory loop of the Jak/STAT pathway, by which STAT1/3 directly activates the expression of many components of this pathway. This feed-forward loop provides a positive mechanism to direct the progenitor stem cells toward astrogliogenesis, showing that sufficient activation of the Jak/ FIGURE 14.…”

Leukemia Inhibitory Factor Promotes Neural Stem Cell Self-Renewal in the Adult Brain

“…LIF may promote glial cell fate at the expense of the neuronal lineage in vivo, as it does in vitro (Bonni et al, 1997;Chang et al, 2004;Barnabe-Heider et al, 2005;He et al, 2005), which could explain the depletion of neuronal cells in the SVZ. Consistent with this hypothesis, phenotypic analysis in periventricular areas and the cortex of Ad:LIF-treated animals reveals a threefold to fivefold increase in BrdUϩ cells expressing Olig2 or S100, two glial cell markers (Fig.…”

“…LIF signaling activates the Jak (Janus kinase)/STAT (signal transducer and activator of transcription) and MAP (mitogen-activated protein) kinase pathways, which promote astrogliogenesis in vitro (Bonni et al, 1997;Molne et al, 2000;Viti et al, 2003;Chang et al, 2004;Barnabe-Heider et al, 2005;He et al, 2005). In addition, LIF is well known for promoting mouse embryonic stem (ES) cell selfrenewal (Williams et al, 1988) and the long-term growth of embryonic human NSCs in culture (Wright et al, 2003).…”